The purpose of this Program Project Grant is to develop more selective and ultimately specific forms of immunosuppression for human organ transplantation. Clearly, this effort will be guided by our basic understanding of the allogeneic immune response and the mechanisms by which it destroys foreign tissue. This project is designed to explore these fundamental issues of biology. The experiments in this project will focus on a single example of graft rejection-the destruction of male skin grafts by female members of inbred strains of mice. This example, which depends on recognition of the H-Y minor histocompatibility antigen, has several powerful features: a) the response to this single antigen can be determined in every inbred strain; b) some strains have been identified as responders while other are non-responders to the H-Y antigen; c) recognition of this antigen requires processing and presentation in association with MHC antigens; and d) H-Y graft rejection is relatively slow and easily manipulated allowing investigation of memory responses which speed rejection or of interventions which prevent it entirely. While many others have studied H-Y graft rejection, their work so far has captured only a small portion of the potential contribution this system has to offer. These studies will begin by correlating the ability of different mouse strains to reject male skin grafts in vivo with the development of different T cell functions in vitro. The experiments will use several standard techniques of modern cellular immunology, which have not yet been applied to the analysis of the H-Y response, to examine the mechanism of graft rejection. Second, experiments will take advantage of the requirement for H-Y antigen presentation to investigate the special features of rejection when it depends on recognition of the foreign antigen in association with recipient MHC antigens. Third, H-Y graft rejection will be used to screen new forms of immunosuppression (such as are being or could be used in other projects of this Program Project) to learn more about the mechanisms of rejection and about the effectiveness of these new approaches depending on the mechanisms involved. Fourth, experiments will determine the nature of sensitized T cells for H-Y antigens, testing their requirements for activation and for suppression. Finally, studies taking advantage of the relative ease with which H-Y rejection can be diminished, will investigate the signals which allow down-regulation rather than activation of T cell responses.